Klippel–Feil syndrome is a rare disease, initially reported in 1884 by Maurice Klippel and André Feil from France,[1] characterized by the congenital fusion of any two of the seven cervical vertebrae.[2]:578 The syndrome occurs in a heterogeneous group of patients unified only by the presence of a congenital defect in the formation or segmentation of the cervical spine. Klippel-Feil results in limited movement of the neck. Klippel–Feil syndrome is sometimes identified by shortness of the neck, but not all people with this disorder have a visibly shortened neck. Some people with the syndrome have a very low hairline.[3] In 1919, in his PhD thesis,[4] André Feil suggested another classification of the syndrome encompassing not only deformation of the cervical spine but also deformation of the lumbar and thoracic spine.

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Numerous associated abnormalities of other organ systems may be present. This heterogeneity requires comprehensive evaluation of all patients and treatment regimes that can vary from modification of activities to extensive spinal surgeries. Furthermore, it is unclear whether Klippel–Feil syndrome is a unique disease, or if it is one part of a spectrum of congenital spinal deformities. Klippel–Feil syndrome is usually diagnosed after birth.

The most common sign of the disorder is restricted mobility of the neck and upper spine. A short neck and low hairline at the back of the head may occur in some patients.

Approximately 35% of patients with Klippel–Feil syndrome will also have a congenital elevation of the scapula known as Sprengel's deformity[7]

The disorder also may be associated with abnormalities of the head and face, skeleton, sex organs, muscles, brain and spinal cord, arms, legs, fingers and heart defects. These heart defects often lead to a shortened life expectancy, the average being 35–45 years of age among males and 40–50 among females.[citation needed] This condition is similar to the heart failure seen in gigantism.[8]

In 2011, a study identifying the occurrence of symptoms of 100 patients was published.[9]

Genetic genealogy has identified a specific location of a gene on a chromosome for Klippel-Feil Syndrome. Mutations in the GDF6 and GDF3 genes have also been identified to cause the disease, although some people with Klippel–Feil syndrome do not have identified mutations in the GDF6 or GDF3 genes. In this case, the cause of the condition in these individuals is unknown. GDF6 and GDF3 genes provide the body with instructions for making proteins involved in regulating the growth and maturation of bone and cartilage. These proteins actively regulate cell growth in embryonic and adult tissue. GDF6 specifically is involved in the formation of vertebral bones, among others, and establishing boundaries between bones in skeletal development while GDF3 is involved with bone and cartilage growth. Mutations cause reductions in these functional proteins but, it is unclear exactly how a shortage in these proteins leads to incomplete separation of the vertebrae in people with Klippel–Feil syndrome.[10] However, when the GDF6 gene was knocked out in mice, the result was the fusion of bones.[11] Only by identifying the link between the genetic cause and the phenotypic pathoanatomy of Klippel–Feil syndrome will we be able to rationalize the heterogeneity of the syndrome.

These mutations can be inherited in two ways:

Autosomal dominant inheritance, where one copy of the altered gene in each cell is sufficient to cause the disorder, is especially associated with C2-C3 fusion.[10]

Autosomal recessive inheritance, where both copies of a gene contain mutations, is especially associated with C5-C6 fusion.[10]

Another autosomal dominant form (mapped on locus 8q22.2) known as Klippel–Feil syndrome with laryngeal malformation has been identified. It is also known as Segmentation syndrome 1.[12][13]

In 1912, Maurice Klippel and Andre Feil independently provided the first descriptions of Klippel–Feil syndrome. They described patients who had a short, webbed neck; decreased range of motion (ROM) in the cervical spine; and a low hairline. Feil subsequently classified the syndrome into 3 categories:

Type I — Fusion of C2 and C3 with occipitalization of the atlas. Further complications were later reported by McRae in 1953. Flexion and extension is concentrated within the C1 and C2. As with aging, an odontoid can become hypermobile, which narrows the spinal cord and brain stem.

Type II — Long fusion below C2 with an abnormal occipital-cervical junction. Similar to the C2-C3 fusion of McRae and could be reviewed as a more elaborate variation. Flexion, extension, and rotation are all concentrated in the area of the abnormal odontoid or poorly developed ring of C1 which cannot withstand the effects of aging. Difference in pattern from the patient with a long fusion and a normal C1-C2 articulation, is that C1-C2 can live a normal life expectancy.

Type III — A single open interspace between two fused segments. Cervical spine motion is concentrated at single open articulation. This hypermobility may lead to instability or degenerative osteoarthritis. This pattern can be recognized as the cervical spine is often seen to be at an angle or hinge at this open segment.

However, recently, Dino Samartzis and colleagues in 2006 proposed 3 classification-types that specifically addressed the cervical spine anomalies and their associated cervical spine-related symptoms, with additional elaboration on various time-dependent factors regarding this syndrome.[15]

Treatment for Klippel–Feil syndrome is symptomatic and may include surgery to relieve cervical or craniocervical instability and constriction of the spinal cord, and to correct scoliosis.[citation needed]

Failing non-surgical therapies, spinal surgery may provide relief. Adjacent segment disease and scoliosis are two examples of common symptoms associated with Klippel–Feil syndrome, and they may be treated surgically. The three categories treated for types of spinal cord deficiencies are massive fusion of the cervical spine (Type I), the fusion of 1 or 2 vertebrae (Type II), and the presence of thoracic and lumbar spine anomalies in association with type I or type II Klippel–Feil syndrome (Type III).

Adjacent segment disease can be addressed by performing cervical disc arthroplasty using a device such as the Bryan cervical disc prosthesis.[16] The option of the surgery is to maintain range of motion and attenuate the rate of adjacent segment disease advancement without fusion.[17] Another type of arthroplasty that is becoming an alternate choice to spinal fusion is Total Disc Replacement. Total disc replacement objective is to reduce pain or eradicate it.[18]Spinal fusion is commonly used to correct spinal deformities such as scoliosis. Arthrodesis is the last resort in pain relieving procedures, usually when arthroplasties fail.

The heterogeneity of the Klippel–Feil syndrome has made it difficult to outline the diagnosis as well as the prognosis classes for this disease. Because of this, it has complicated the exact explanation of the genetic cause of the syndrome.

The prognosis for most individuals with KFS is good if the disorder is treated early on and appropriately. Activities that can injure the neck should be avoided, as it may contribute to further damage. Other diseases associated with the syndrome can be fatal if not treated, or if found too late to be treatable.[19]

The prevalence of Klippel–Feil syndrome is unknown due to the fact that there was no study done to determine the true prevalence.[20]

Although the actual occurrence for the KFS syndrome is unknown, it is estimated to occur 1 in 40,000 to 42,000 newborns worldwide. In addition, females seem to be affected slightly more often than males.[10]

In 2009, archaeologists excavating at a Neolithic site of the Đa Bút culture of northern Vietnam discovered the remains of a young man around age 25, "Burial 9", living between 2000 BC and 1500 BC with Klippel–Feil syndrome, who had apparently been supported by his subsistence-level community for at least a decade before his death.[22][23][24]

The 18th Dynasty Egyptian pharaohTutankhamun is believed by some to have suffered from Klippel–Feil syndrome,[25] though others dispute this claim.[26]